The primary aim of the proposed center is to develop and evaluate pre-cessation adaptive treatments for cigarette addiction. The overarching goal of this project is to evaluate the neural mechanisms that underlie pre-cessation medication effects. In a design paralleling Project 1. Clinical Trials (PD: Rose), 100 smokers will be assigned to one of four treatment arms. In all four arms, participants will continue to smoke their usual brand of cigarettes in the two weeks prior to quitting smoking. The control (CNTRL) group will wear a placebo patch in the two weeks prior to their quit date. A second group will wear a 21 mg/d patch for the two weeks prior to the quit date (NRT-Only). A third group will switch from wearing a nicotine patch to taking varenicline in the second week (NRTVAR). A fourth group will take bupropion SR in addition to NRT in the second week (NRT+BUP). Participants will be scanned at baseline and again 12 hrs after quitting smoking. During scanning, we will measure brain reactivity to smoking cues and cerebral blood flow. Common and unique effects of pre-cessation pharmacotherapies will be identified. Based on preliminary data, we hypothesize that pre-cessation treatment will result in lower brain reactivity to smoking cues and cerebral blood flow following quitting smoking. We also hypothesize that baseline brain function will be predictive of pre- and post-quit treatment response. The proposed project builds upon the investigative team's experience and is highly integrated with the center's other projects and cores.